Discovery of novel spiro[chromane-2, 4′-piperidine] derivatives as potent and orally bioavailable G-protein-coupled receptor 119 agonists. Issue 19 (15th October 2018)

• Record Type: Journal Article
• Authors: Koshizawa, Tomoaki; Morimoto, Toshiharu; Watanabe, Gen; Fukuda, Tomoaki; Yamasaki, Nao; Hagita, Sumihiko; Sawada, Yoshikazu; Okuda, Ayumu; Shibuya, Kimiyuki; Ohgiya, Tadaaki
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 19(2018)
• Page Start: 3236
• Page End: 3241
• Publication Date: 2018-10-15
• Subjects: GPR119 agonists -- Type 2 diabetes mellitus -- Spiro[chromane-2, 4′-piperidine] -- Biphenyl; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.08.010
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: The spiro-type scaffold was used as a novel linker-to-tail moiety of GPR119 agonists. The rigid spiro-type scaffold enabled flexible and successful optimization. Optimized( R )-29 exhibited a potent in vivo activity sufficient for a drug candidate. Abstract: Herein, we describe the discovery, synthesis, and evaluation of a novel series of spiro[chromane-2, 4′-piperidine] derivatives as G-protein-coupled receptor 119 agonists. Their initial design exploited the conformational restriction in the linker-to-tail moiety, which was a key concept in this study, to give lead compound11 (EC50 = 369 nM, E max = 82%). An extensive structure–activity relationship study resulted in the identification of the optimized drug candidate( R )-29 (EC50 = 54 nM, E max = 181%). The defining structural features of the series were a terminal benzyl-type bulky substituent and a methylene linker between the sulfonyl and phenyl groups, both of which were in the head moiety as well as the spiro-type scaffold in the linker-to-tail moiety. An in vivo oral glucose-tolerance test using C57BL/6N mice showed that( R )-29 reduced glucose excursion at a dose of 3 mg/kg in a dose-dependent manner.